Neuroimaging techniques have provided effective tools for investigating the influence of pain on CNS function. Human imaging studies have identified a pain matrix composed of brain regions that are activated by nociceptive stimuli. Activation is observed in the secondary somatosensory and insular regions, the anterior cingulate as well as the primary somatosensory area and thalamus. More limited evidence indicates decreased activity in a network that includes the inferior parietal lobule, and the medial prefrontal cortex. These regions are thought to subserve discriminative sensory pain transmission and to process affective-motivational components of pain. MRI investigations in chronic neuropathic pain indicate brain neurodegeneration and decreased gray matter volume and density in patients with chronic back pain, phantom pain, or fibromyalgia, although degree and regional distribution varies. Chronic back pain patients show activation of the prefrontal cortex during spontaneous pain, the same area that shows a reduction in gray matter density, as well as disruption in resting functional connectivity of widespread cortical areas. The nature of structural changes remains to be determined, whether neurodegeneration is causal and if analgesics prevent these changes. A difficulty in human research is assembling a homogenous patient cohort with matched symptoms, disease duration, medication history and age distribution. Since subjects are not tested prior to pain onset, individual differences that may predispose pain vulnerability can not be assessed. Importantly, the response to nerve injury and to different treatments varies among patients with comparable pain syndromes and not all patients exhibit neuropathic pain behavior after a demonstrable nerve injury. For these reasons, human functional imaging has not yet provided reproducible findings specific to the disease or a pathophysiological basis for symptomology. Prior to the advent of small animal imaging, preclinical studies could not directly measure spontaneous pain, a limitation in their utility as models of neuropathic pain. However, procedural advances now allow quantification of alterations in resting state connectivity and stimulus-evoked activity. The coupling of imaging to animal models of neuropathic pain allows longitudinal study of the development of pain and its expression. Changes in brain function that occur during spontaneous and stimulus-evoked pain can be assessed as a function of pain duration: grey matter volume and white matter integrity can be assessed over time. Using MRI and MRS techniques and the spared nerve injury (SNI) model of neuropathic pain in rats, ongoing studies seek to: i) identify changes in brain structure, function and metabolism that occur in the pain matrix as a function of the duration of neuropathic pain;ii) determine whether individuals differ in vulnerability to SNI-evoked pain and whether these differences are associated with differences in brain function and iii) determine whether a manipulation that we have shown to prevent the development of or reverse the expression of SNI-evoked allodynia and hyperalgesia (see below) reduces SNI-evoked alterations in spontaneous and evoked brain activity, functional connectivity, concentrations of biochemical compounds, grey matter volume and white matter integrity. Using advanced MRI and MRS techniques developed within the IRP, we expect to identify maladaptive brain plasticity at a systems level in the SNI rats, and to correlate brain plasticity with behavioral pain measures. The proposed translational studies will enable identification of a disease-modifying strategy aimed at both preventing maladaptive plasticity and identifying intrinsic risk individuals The rostral ventromedial medulla (RVM) constitutes the efferent component of pain-control systems that descend from the brain to the spinal cord. Considerable evidence has emerged regarding participation of this system in persistent pain conditions such as inflammation and neuropathy. The RVM normally exerts an inhibitory influence on dorsal horn neurons However, persistent noxious stimulation triggers time-related alterations in RVM synaptic activity. In inflammatory pain models, descending facilitation transiently increases reducing the net effect of inhibition. Over time, descending inhibition increases resulting in decreased nocifensive behavior. After nerve injury, RVM plasticity leads to facilitation of spinal cord nociceptive output, exacerbation of primary hyperalgesia and enhanced sensory input from adjacent regions (secondary hyperalgesia). AMPA receptor activation in the RVM has been shown to inhibit spinal nociceptive transmission and nocifensive behavior. Increased AMPA receptor function in the RVM is implicated in the activity-dependent plasticity that occurs in response to persistent pain produced by tissue inflammation. Targeting and synaptic clustering of AMPA receptors is essential for efficient excitatory transmission. Neuronal pentraxin 1 (NP1) is a member of the pentraxin family of proteins that is expressed exclusively in neurons and facilitates AMPA receptor clustering. Given the postulated role of NP1 in excitatory synaptic transmission and AMPA receptor systems in pain processing, we have used gene deletion and viral-mediated transfer techniques to examine whether manipulations that target this protein can affect the expression of persistent pain. To determine the contribution of NP1 to nerve-injury evoked pain, we assessed mechanical hypersensitivity in wild type and NP1 knock out mice following spared nerve injury. Nerve injury led to marked mechanical hypersensitivity of the injured limb. This enhanced nociception is significantly inhibited in NP1 knockout mice. In order to probe the specific involvement of RVM NP1 in mediating the attenuated response of NP1 knockout mice, we infused a lentiviral vector which drives expression of functional NP1 protein directly into the RVM. Selective rescue of RVM NP1 expression in knockout mice restores allodynia produced by nerve injury. Consistent with the data obtained in NP1 knockout mice, silencing NP1 expression in the RVM of rats prior to nerve injury inhibits allodynia. Furthermore, it decreases mechanical hyperalgesia. These findings are consistent with the observation that descending facilitatory systems arising in the RVM are necessary for the maintenance of neuropathic pain and identify NP1 in the RVM as a critical element in the descending facilitation of nerve-injury evoked pain. Together, these data suggest that targeting NP1 may be a novel therapeutic strategy for reversing persistent pain of diverse etiologies. On-going studies examining the role of NP1 in other conditions including those associated with AIDS antiretroviral therapy and peripheral inflammation indicate a key role of this protein in the development of persistent pain. Preliminary studies examining the contribution of another pentraxin, pentraxin 3 suggest a global role of the pentraxin family of proteins in the pathogenesis of nerve injury, neuropathic and inflammatory pain.